rs764685377

Positions:

• chr5-90653517-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4 BP6

The NM_032119.4(ADGRV1):​c.3943C>A​(p.Gln1315Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,622 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.31

Genes affected

ADGRV1 (HGNC:17416): (adhesion G protein-coupled receptor V1) This gene encodes a member of the G-protein coupled receptor superfamily. The encoded protein contains a 7-transmembrane receptor domain, binds calcium and is expressed in the central nervous system. Mutations in this gene are associated with Usher syndrome 2 and familial febrile seizures. Several alternatively spliced transcripts have been described. [provided by RefSeq, Jul 2008]

ADGRV1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26693225).
• BP6: Variant 5-90653517-C-A is Benign according to our data. Variant chr5-90653517-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 504579.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRV1	NM_032119.4	c.3943C>A	p.Gln1315Lys	missense_variant	20/90	ENST00000405460.9	NP_115495.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRV1	ENST00000405460.9	c.3943C>A	p.Gln1315Lys	missense_variant	20/90	1	NM_032119.4	ENSP00000384582.2
ADGRV1	ENST00000640403.1	c.1234C>A	p.Gln412Lys	missense_variant	10/29	5		ENSP00000492531.1
ADGRV1	ENST00000504142.2	n.2709C>A		non_coding_transcript_exon_variant	14/14	5
ADGRV1	ENST00000639676.1	n.1541C>A		non_coding_transcript_exon_variant	8/11	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000803 AC: 2 AN: 248980 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135058

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461622 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727082

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000189

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 30, 2018

The p.Gln1315Lys variant in ADGRV1 has not been previously reported in individua ls with hearing loss or Usher syndrome, but was identified in 1/15284 African ch romosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitu te.org; dbSNP rs764685377). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Comp utational prediction tools and conservation analyses do not provide strong suppo rt for or against an impact to the protein. In summary, the clinical significanc e of the p.Gln1315Lys variant is uncertain. ACMG/AMP Criteria applied: PM2. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T;T;.
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.69	.;T;T
M_CAP	Uncertain	0.090	D
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-0.41	T
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.6	.;N;.
REVEL	Benign	0.16
Sift	Benign	0.081	.;T;.
Sift4G	Benign	0.063	.;T;.
Polyphen		0.94	P;P;.
Vest4		0.64
MutPred		0.45		Gain of methylation at Q1315 (P = 0.0093);Gain of methylation at Q1315 (P = 0.0093);.;
MVP		0.55
MPC		0.057
ClinPred		0.32	T
GERP RS		5.4
Varity_R		0.47
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs764685377; hg19: chr5-89949334;